Regulatory Mochanisms For Proliferation, Differentiation, And Apoptosis of Leukemic Cells In Reference To Cell Cycle Phases.

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During the period from 1994 to 1995, the following new findings were obtained, and most of them were presented in some of the international conferences. and published in the specialized journals : (1) The inhibitory activity of TGF-beta on the growth of human monoblastic cell line JOSK-I cells was observed at the late G1 phase, but not at the S or G2/M phase of cell cycle. TGF-beta did not affect the level of both mRNA and protein of cdc2 gene, but did inhibit the translation rate of cdc2 gene and the cdc2 kinase activity. Thus, the growth inhibition by TGF-beta was closely related to the inhibition of RB protein (Rb) phosphorylation (the significant storage of unphosphorylated Rb) followed by the inhibition of DNA synthesis, and the unphosphorylated Rb storage was suggested to occur through the inhibition of cdc2 kinase activity by TGF-beta. On the other hand, the growth inhibitory activity of aphidicoline was observed at the G1/S phase with little unphosphorylated Rb. The differentia … More tion-inducer, phorbol ester TPA,also did unphosphorylate Rb protein, which was suggested to occur in the differentiation induction followed by the cell cycle arrest. With all these data together, it was suggested that some cdc2 gene products or an unidentified Rb kinase might be intimately involved in the Rb phosphorylation. (2) The experimental model system was established, in which, using human myelogenous leukemia cell line HL-60 cells, the differentiation induction (the differentiation commitment and the expression of differentiation properties) and the apoptosis induction could be separately analyzed. The results obtained were as follows : the NBT reducing acitivity and the apoptosis induction were independently observed, and the expression of both myc and bcl-2 genes was inhibited 6 hrs after the initiation of differentiation induction. During the period of 24-36 hrs after the initiation of differentiation induction, all the events necessary for the apoptosis induction occurred closely relating to the inhibition of bcl-2 expression. (3) The biological function of the extracellular matrix (ECM) glycoprotein, tenascin, was investigated since ECM glycoproteins in general have recently become clarified to play an important role in the regulation of cell proliferation and differentiation through the cell-to-cell adhesion and recognition. The expression of tenascin-C was termporally and spatially regulated in the strict manner at the stromal-epithelial interactions observed in tumor formations. Although the physiological regulators for tenascin-C expression-induction are still unknown, the do novo synthesis of tenascin-C in the stromal-epithelial interactions was induced with the soluble epithelial growth factor (EGF), and this induction was inhibited with steroid hormons such as hydrocortisone. Some stromal cell lines, which were deficient in the tenascin-C expression, could be first established from the bone marrows of tenascin-C gene knock-out mice, and then, usi Less